Selective sulphonation of the primary alcohol of a diol containing both primary and secondary alcohols

ABSTRACT

This invention discloses an efficient process for selectively sulfonating the primary alcohol of a diol containing both primary and secondary alcohols.

This application is a 371 of PCT/US97/15702 filed Sep. 5, 1997, whichclaims benefit of U.S. Provisional Application No. 60/025,523 filed onSep. 6, 1996.

This invention relates to the fields of pharmaceutical and organicchemistry and provides a new catalytic process for the selectivesulfonylation of a primary alcohol in the presence of a secondary orunactivated alcohol.

An efficient process for selectively sulfonating a primary alcohol in asubstrate that also contains a secondary alcohol is desired for thesynthesis of key intermediates to important pharmaceutical agents.Normal methods of sulfonating such a diol use a base withtoluenesulfonyl chloride. As shown in Equation 1, the normal methodresults in a mixture of the desired primary tosylate (2), a secondarytosylate (3), and a bis-tosylate (4), as well as the starting diol (1)(eq 1).

The present invention provides an improved process for preparing acompound of formula I

wherein

R¹ is H or R²; and

R² is C₁-C₁₂ alkyl; C₂-C₁₂ alkenyl, C₃-C₈-cycloalkyl, aryl, aryl-(C₁-C₆alkyl), aryl-Z—(C₁-C₆ alkyl), heteroaryl, heteroaryl-(C₁-C₆ alkyl), orheteroaryl-Z—(C₁-C₆ alkyl), any of which may have up to three R⁵substituents; or

R¹ and R² together complete a 5-6-membered ring that may have up tothree R⁵ substituents;

R⁵ is C₁-C₁₂ alkyl, halo, hydroxy or C₁-C₃ alkoxy;

n is 0, 1 or 2;

Z is 0 or S; and

R^(p) is C₁-C₆ alkylsulfonyl or arylsulfonyl comprising contacting

a) a compound of formula II

with

b) a compound of formula R^(p)SO₂X or (R^(p)SO₂)₂O

wherein X is halo or imidazolyl;

c) a tertiary amine; and

d) a catalytic quantity of a compound of formula (R^(a))₂Sn (X^(a)) m;

wherein

R^(a) is C₁-C₁₂ alkyl;

X_(a) is O, Cl, Br, OAc or OR^(b);

m is 1 or 2; and

R^(b) is C₁-C₆ alkyl or aryl.

A preferred aspect of this invention is a process for selectivelytosylating a primary alcohol in the presence of a secondary alcoholcomprising reacting the primary alcohol with tosyl chloride in thepresence of a catalytic quantity of Sn(IV).

The use of tin(IV) in a catalytic amount rather than in a stoichiometricamount provides important advantages. Reactions using a stoichiometricamount of tin require extensive chromatography to remove unwanted,lipophilic tin oxide. Even after such purification steps, about one toten mole percent (1-10%) of tin contaminants remain. Such compromisedproduct quality significantly limits the use of stannylene methodologyin the preparation of pharmaceuticals.

Products produced by the process of this invention can be purified usinga brief rinse and solvent removal. Additionally, the product containsdramatically less tin contaminant (less than 0.1 mole percent).

Thus, the present process provides the needed selectivity and gives apharmaceutically acceptable intermediate that has <0.1 mole percent tincontaminant.

Preferred diol intermediates are those that are useful for preparingcryptophycin compounds.

Preferred tin catalysts are tin oxides. Particularly useful tin oxidesare dibutyltin oxide and dibutyltin dimethoxide.

The present invention also provides a process for deracemizing ameso-diol comprising reacting such a diol with a chiral tin (IV)reagent.

The phrase “catalytic quantity” is understood in the art. It refers toan amount that is less than a stoichiometric amount, but is sufficientto achieve the desired results.

The term “alkyl” refers to an alkyl group with the designated number ofcarbon atoms. It may be saturated or unsaturated, branched or straightchain. Examples of alkyl groups include methyl, ethyl, n-propyl,iso-propyl, n-butyl, propenyl, ethenyl, sec-butyl, n-pentyl, isobutyl,tert-butyl, sec-butyl, methylated butyl groups, pentyl, tert pentyl,sec-pentyl, methylated pentyl groups and the like.

The term “alkenyl” refers to an alkyl group having from one to threedouble bonds. “Cycloalkyl” refers to a saturated C₃-C₁₂ cycloalkylgroup.

The term, “alkoxy” means a straight or branched alkyl group bonded to anoxygen atom.

The term “aromatic group” and “heteroaromatic group” refer to commonaromatic rings having 4n+2 pi electrons in a monocyclic conjugatedsystem or a bicyclic conjugated system. The term “aryl” refers to anaromatic group. Examples of aromatic groups are phenyl, benzyl andnaphthyl. Heteroaromatic groups will contain one or more oxygen,nitrogen and/or sulfur atoms in the ring. Examples of heteroaromaticgroups include furyl, pyrrolyl, thienyl, pyridyl and the like. When thearomatic or heteroaromatic groups are substituted, the substituents maybe attached at any available carbon atom.

The term “halo” refers to Cl, Br, F, or I.

One example of the process of this invention is shown in Equation 2

Product 6 was tosylated selectively and cleanly under the catalytic tinconditions (<1% bis-tosylate), wherein in the absence of tin, thereaction was neither selective nor clean (>10% bis-tosylate).

Thus, tin in catalytic amounts efficiently accelerates theregioselective protection of primary alcohols. This method obviates theneed for extensive chromatographic purification and provides a productwith minimal tin contamination.

The process of this invention is applicable to a variety of alcoholsubstrates and is particularly useful for the synthesis of a keyintermediate for the production of cryptophycin compounds.

Examples of formula II substrates include:

In these examples, Ar is as defined supra, and

The process of this invention is carried out in the presence of atertiary amine. The tertiary amine can be represented by R₃N, wherein Rcan be alkyl or aryl or the R₃ unit together with the N represents aring, such as pyridine or piperidine. Trialkylamines are preferred, andtriethylamine is especially preferred. Diisopropylethylamine andpyridine can also be used.

The process of this invention is preferably carried out in the presenceof a solvent, such as an inert organic solvent. Dichloromethane is anespecially preferred solvent. Other solvents that can be used areacetonitrile, which is better than tetrahydrofuran, which is better thantoluene, which is still better than methanol.

The specificity of the process of this invention is illustrated in Table1, which compares the tosylation of diol 5 with and without tin as acatalyst:

TABLE 1 Comparison of Bis-Tosylate Formation with Tin Catalysis WithoutTin With Tin Reagent Catalysis Catalysis diol 5 1.0 mole 1.0 mole TsCl1.0 mole 1.0 mole Et₃N 1.0 mole 1.0 mole Bu₂Sn = O 0 0.001 mole % bistosylate >10% <1%

An especially preferred feature of the improved process is that it makespossible a shorter and more efficient synthesis of cryptophycincompounds than the known synthetic method. See Barrow, et al. J. Am.Chem. Soc. 1995, 117, 2479-2490. The process also is useful in preparingmodified cryptophycin compounds of formula I

wherein

G is C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl or Ar;

Ar is an aromatic or heteroaromatic group or a substituted aromatic orheteroaromatic group;

R¹ is halo, SR, OR, amino, mono or di-(C₁-C₆-alkyl)amino, tri(C₁-C₆-alkyl) ammonium, C₁-C₆-alkylthio, di (C₁-C₆-alkyl)sulfonium,C_(l)-C₆-alkylsulfonyl, or C₁-C₆-alkylphosphonyl and

R² is OH or SH; or

R¹ and R² taken together form a second bond between C-18 and C-19 ortogether form an epoxide, aziridine, episulfide, or cyclopropyl ring;

R is H, C₁-C₆ alkyl, C₁-C₆ alkanoyl or Ar;

R³ is C₁-C₆ alkyl;

R⁴ and R⁵ are H; or

R⁴ and R⁵ taken together form a second bond between C-13 and C-14;

R⁷ is H, C₁-C₆ alkyl NR⁵¹R⁵², -(C₁-C₃-alkyl)NR⁵¹R⁵², or OR⁵¹; and

R⁸ is H or C₁-C₆ alkyl; or

R⁷ and R⁸ together form a cyclopropyl ring;

R⁵¹ and R⁵² independently are C₁-C₃ alkyl;

R⁹ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆-alkynyl or (C₁-C₆ alkyl)C₃-C₅ cycloalkyl;

R¹⁰ is H or C₁-C₆ alkyl;

R¹⁴ is H or a lower alkyl group;

X is O, NH or (C₁-C₃ alkyl)N—;

Y is C, O, NH, S, SO, SO₂ or (C₁-C₃ alkyl)N—;

R⁶ is C₁-C₆ alkyl, substituted (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,substituted C₃-C₈ cycloalkyl, a heteroaromatic or substitutedheteroaromatic group, or a group of formula IIIa, III′ or III″:

R^(6a), R^(6b), and R^(6c) independently are H, halo or OR¹⁸;

R¹⁵, R¹⁶, and R¹⁷ independently are hydrogen, halo, (C₁-C₆)alkyl, OR¹⁸,O-aryl, NH₂, NR¹⁸R¹⁹, NO₂, OPO₄H₂, (C₁-C₆ alkoxy)phenyl, Sbenzyl, CONH₂,CO₂H, PO₃H₂, SO₂R²³, or Z′;

R¹⁸ and R¹⁹ independently are hydrogen or C₁-C₆ alkyl;

R²³ is hydrogen or (C₁-C₃)alkyl;

Z is —(CH₂)_(n)— or (C₃-C₅)cycloalkyl;

n is 0, 1, or 2; and

Z′ is an aromatic or substituted aromatic group;

Additionally, when the process uses a tin oxide, it can be used toderacemize meso-diols using a chiral Sn═O reagent. The chiral Sn═Oreagent can be prepared using chiral ligands bound in a covalent fashionor through chiral amines added to the reaction mixture which would bindto the Sn center.

Some preferred processes of this invention are those wherein:

A) the diol is of the formula:

B) the tin catalyst is a tin oxide;

C) the tin catalyst is dibutyltin oxide or dibutyltin dimethoxide;

D) the process is completed in the presence of a solvent;

E) the process uses a chiral Sn(IV) reagent to provide deracemization ofmeso-diols;

F) the process is used to prepare an intermediate which is useful forthe preparation of a cryptophycin compound; and

G) the process is used to prepare an intermediate which is useful forthe preparation of a cryptophycin compound of Formula I.

Appropriate starting materials and reagents used to prepare the desiredsubstrates, and the reagents used in the processes can be selected usingthe guidance of the previous schemes and following examples. Most of thereagents are commercially available, and those which are not can beprepared using accepted chemical methods.

The necessary reaction time is related to the starting materials andtemperature used. The optimum reaction time for a given process is, asalways, a compromise which is determined by considering the competinggoals of throughput, which is favored by short reaction times, andmaximum yield, which is favored by long reaction times.

To further illustrate the invention the following non-limiting examplesare provided.

EXAMPLE 1 Preparation of Primary Tosylate 6. (See Eq. 2)

To a 2-L 3-necked round-bottom flask, equipped with a mechanical stirrerand nitrogen inlet, was added diol 5 (58 g, 0.30 mol), Bu₂Sn═O (1.5 g,0.0060 mol), CH₂Cl₂ (580 mL), Et₃N (30.5 g, 0.30 mol) and TsCl (57.5 g,0.30 mol). The reaction mixture was stirred at room temperature untilchromatographic analysis indicated the reaction was complete (within30-40 minutes). The reaction mixture was filtered over a pad of Hy-flo,and the filtrate was washed with water, dried over MgSO₄ andconcentrated to yield compound 6 as a clear slightly amber oil (99%).

What is claimed is:
 1. In the process for preparing a compound offormula I:

wherein R¹ is H; and R² is C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl,C₃-C₈cycloalkyl, C₁-C₁₀ alkoxy, aryl, aryl-(C₁-C₆ alkyl), aryl-Z—(C₁-C₆alkyl), heteroaryl, heteroaryl-(C₁-C₆ alkyl), or heteroaryl-Z—(C₁-C₆alkyl), each of which may contain zero to three R⁵ substituents; or R¹and R² together complete a 5-6-membered ring that may have up to threeR⁵ substituents; R⁵ is C₁-C₁₂ alkyl, halo, hydroxy or C₁-C₃ alkoxy; N is0, 1, or 2; Z is 0 or S; and R^(p) is C₁-C_(?) alkylsulfonyl orarylsulfonyl comprising reacting a) a compound of formula II

with b) a compound of formula R^(p)SO₂X or (R^(p)SO₃)₂O wherein X ishalo or imidazolyl; and c) a tertiary amine, the improvement comprisingadding d) a catalytic quantity of a compound of the formula(R^(a))₂Sn(X^(a))_(m) wherein R^(a) is C₁-C₁₂ alkyl; X^(a) is O, Cl, Br,OAc or OR^(b); m is 1 or 2; and R^(b) is C₁-C₆ alkyl or aryl.
 2. Animprovement of claim 1 wherein n is zero.
 3. An improvement of claim 1wherein R² is aryl (C₁-C₆) alkyl-.
 4. An improvement of claim 1 whereinthe R^(p)SO₂ group is tosyl.
 5. An improvement of claim 1 wherein X ischloro.
 6. An improvement of claim 1 wherein X^(a) is
 0. 7. Animprovement of claim 1 wherein R^(a) is C₁-C₆-alkyl.
 8. A process fortosylating the primary alcohol of a diol containing both a primaryalcohol and a secondary alcohol comprising reacting said diol with tosylchloride in the presence of a catalytic quantity of tin oxide Sn(IV). 9.The process of claim 8 wherein the Sn(IV) is tin oxide.
 10. The processof claim 9 wherein the tin oxide is dibutyltin oxide or dibutyltinmethoxide.
 11. The process of claim 8 wherein the diol is selected fromthe group consisting of